Riluzole for Glioblastoma [Neurosurgery Wiki]

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====== Riluzole for Glioblastoma ======

In advanced grades of glioblastoma, [[glutamate]] and [[glutamine]] are reported to be increased in concentration in the extracellular fluid. It has been reported that glutamate acts as an [[extracellular signaling molecule]] for facilitating local spread of advanced grades of glioblastoma. 

Glioblastomas exploit various molecular [[pathway]]s to promote   - [[glutamate]]- dependent growth by activating the [[AMPA]] (2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl) propanoic acid) receptor, the group II metabotropic glutamate receptor, mGluR, and the epidermal growth factor receptor, EGFR. Yelskaya et al. hypothesized that targeting more than one of these [[pathway]]s would be more effective in inhibiting glutamate-dependent growth. Using a model of [[U87]] cell line, Yelskaya et al. showed that blocking glutamate release by [[Riluzole]] inhibits [[cell proliferation]]. Glutamate-dependent growth is effectively inhibited by a combination of Iressa, an inhibitor of EGFR activation and LY341495, a group II mGluR inhibitor. Treatment of U87 cells with a combination of Iressa and LY341495 inhibits proliferation as indicated by Ki-67 staining, induces apoptosis and inhibits migration of U87 cells more effectively than the treatment by Iressa or LY341495 alone. These results demonstrate that a combinatorial therapy with Iressa and LY341495 is more effective due to synergistic effects of these drugs in inhibiting the growth of glioblastoma
((Yelskaya Z, Carrillo V, Dubisz E, Gulzar H, Morgan D, Mahajan SS. Synergistic inhibition of survival, proliferation, and migration of U87 cells with a combination of LY341495 and Iressa. PLoS One. 2013 May 27;8(5):e64588. doi: 10.1371/journal.pone.0064588. PMID: 23724064; PMCID: PMC3664620.)).
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Tong et al. aimed to examine whether glutamate uptake mechanisms is impaired in advanced glioblastoma. The possible downregulated mechanisms of glutamate uptake would facilitate persistence of glutamate in the extracellular environment, rather than intracellular uptake. We obtained biobanked human specimens of glioblastoma and tested expression of proteins belonging to the solute carrier families of proteins that are known to function as membrane-located excitatory amino acid like glutamate transporters. The present study provides preliminary evidence of the downregulation of membrane expression of excitatory amino acid transporters solute carrier family 1 member 3 (SLC1A3) and its palmitoylated form in gliosomes, as well as SLC1A2 in the glio-synaptosomes. Compounds like riluzole used in the treatment of amyotrophic lateral sclerosis and the antibiotic ceftriaxone have the potential to facilitate glutamate uptake. These medications may be examined as adjunct chemotherapy in the massively aggressive tumor glioblastoma multiforme
((Tong H, Yu X, Lu X, Wang P. Downregulation of solute carriers of glutamate in gliosomes and synaptosomes may explain local brain metastases in anaplastic glioblastoma. IUBMB Life. 2015 Apr;67(4):306-11. doi: 10.1002/iub.1372. Epub 2015 Apr 24. PMID: 25914026.)).
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Sperling et al. reported that riluzole treatment inhibits the growth of brain tumor stem-like cells enriched cultures isolated from two human glioblastomas. The effects of riluzole on these cells were associated with an inhibition of a poor prognostic indicator: glucose transporter 3 (GLUT3). A decrease in GLUT3 is associated with a decrease in the p-Akt/HIF1α pathway. Further, downregulation of the DNA (Cytosine-5-)-methyltransferase 1 (DNMT1) gene that causes hypermethylation of various tumor-suppressor genes and leads to a poor prognosis in Glioblastoma, was detected. Two hallmarks of cancer cells-proliferation and cell death-were positively influenced by riluzole treatment. Finally, we observed that riluzole reduced the tumor growth in in vivo CAM assay, suggesting it could be a possible synergistic drug for the treatment of glioblastoma
((Sperling S, Aung T, Martin S, Rohde V, Ninkovic M. Riluzole: a potential therapeutic intervention in human brain tumor stem-like cells. Oncotarget. 2017 May 20;8(57):96697-96709. doi: 10.18632/oncotarget.18043. PMID: 29228563; PMCID: PMC5722515.)).
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Viability of U87 MG and 11ST patient-derived GMB cell lines, after valproic acid, tranylcypromine or riluzole alone, in different combinations, as well as combined with standard temozolomide chemotherapy was examined using the MTT assay. Proliferation, mRNA level of tissue factor pathway inhibitor 2 (TFPI2), and cell invasion were evaluated using anti-Ki-67 antibody staining, reverse transcriptase-polymerase chain reaction and xCELLigence system.

The strongest effect on cell viability was achieved by the combination of riluzole with valproic acid (U87MG: 27.2%, 11ST: 25.99%). Tranylcypromine significantly enhanced the effect of temozolomide when used in combination, as did valproic acid. The normally high proliferation of Glioblastoma significantly declined under treatment with valproic acid with tranylcypromine (p=0.01). Finally, we observed reduction of invasion comparing single tranylcypromine to its combination with valproic acid or riluzole
((Sachkova A, Sperling S, Mielke D, Schatlo B, Rohde V, Ninkovic M. Combined Applications of Repurposed Drugs and Their Detrimental Effects on Glioblastoma Cells. Anticancer Res. 2019 Jan;39(1):207-214. doi: 10.21873/anticanres.13099. PMID: 30591460.)).
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Khan et al. demonstrated that pretreatment with the glutamate-release inhibitor riluzole sensitizes glioma cells to radiation and leads to greater cytotoxicity
((Khan AJ, LaCava S, Mehta M, Schiff D, Thandoni A, Jhawar S, Danish S, Haffty BG, Chen S. The glutamate release inhibitor riluzole increases DNA damage and enhances cytotoxicity in human glioma cells, in vitro and in vivo. Oncotarget. 2019 Apr 19;10(29):2824-2834. doi: 10.18632/oncotarget.26854. PMID: 31073373; PMCID: PMC6497458.)).

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In a riluzole-bead coupled binding assay and in surface plasmon resonance imaging analyses, riluzole was found to directly bind to hnRNP A1 and inhibited IRES activity via effects on ITAF/RNA-binding. Riluzole also demonstrated synergistic anti-glioblastoma (Glioblastoma) affects with [[mTOR inhibitor]]s in vitro and in Glioblastoma xenografts in mice. These data suggest that repurposing riluzole, used in conjunction with mTOR inhibitors, may serve as an effective therapeutic option in [[glioblastoma]]
((Benavides-Serrato A, Saunders JT, Holmes B, Nishimura RN, Lichtenstein A, Gera J. Repurposing Potential of Riluzole as an ITAF Inhibitor in mTOR Therapy Resistant Glioblastoma. Int J Mol Sci. 2020 Jan 5;21(1):344. doi: 10.3390/ijms21010344. PMID: 31948038; PMCID: PMC6981868.)).

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Riluzole attenuates [[TMZ]]-induced [[MGMT promoter methylation]] upregulation and enhances the antitumor effect of TMZ in MGMT-positive Glioblastomas. Therefore, combinatorial TMZ/[[riluzole]] treatment is a potentially promising novel therapeutic regimen for MGMT-positive Glioblastomas
((Yamada T, Tsuji S, Nakamura S, Egashira Y, Shimazawa M, Nakayama N, Yano H,
Iwama T, Hara H. Riluzole enhances the antitumor effects of temozolomide via
suppression of MGMT expression in glioblastoma. J Neurosurg. 2020 Mar
13;134(3):701-710. doi: 10.3171/2019.12.JNS192682. PMID: 32168477.)).
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Dučić et al. exploited [[synchrotron]] [[radiation]]-based soft X-ray [[tomography]] and hard X-ray [[fluorescence]] for elemental microimaging of the shock-frozen [[Glioblastoma]] cells. The present study focused instead on the biochemical profiling of live Glioblastoma cells and provides new insight into tumor heterogenicity. They studied bio-macromolecular changes by exploring the live-cell synchrotron-based [[Fourier-transform infrared spectroscopy]] (SR-FTIR) microspectroscopy in a set of three Glioblastoma cell lines, including the patient-derived glioblastoma cell line, before and after riluzole treatment, a medicament with potential anticancer properties. SR-FTIR microspectroscopy shows that Glioblastoma live cells of different origins recruit different organic compounds. The [[riluzole]] treatment of all Glioblastoma cell lines mainly affected carbohydrate metabolism and the DNA structure. Lipid structures and protein secondary conformation are affected as well by the riluzole treatment: cellular proteins assumed cross β-sheet conformation while parallel β-sheet conformation was less represented for all Glioblastoma cells. Moreover, they hoped that a new live-cell approach for Glioblastoma simultaneous treatment and examination can be devised to target [[cancer cell]]s more specifically, i.e., future therapies can develop more specific treatments according to the specific bio-macromolecular signature of each tumor type
((Dučić T, Ninkovic M, Martínez-Rovira I, Sperling S, Rohde V, Dimitrijević D, Jover Mañas GV, Vaccari L, Birarda G, Yousef I. Live-Cell Synchrotron-Based FTIR Evaluation of Metabolic Compounds in Brain Glioblastoma Cell Lines after Riluzole Treatment. Anal Chem. 2021 Dec 29. doi: 10.1021/acs.analchem.1c02076. Epub ahead of print. PMID: 34965097.)).